The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes

Aim/hypothesis: Glucagon-like peptide-1 (GLP-1) is metabolised by the enzyme dipeptidyl-peptidase 4 (DPP-4), generating a metabolite with potential antagonistic properties. This study was conducted to evaluate the effect of that metabolite on plasma glucose levels in patients with type 2 diabetes. Materials and methods: The randomised crossover study consisted of five regimens: ( 1) i.v. infusion of GLP-1 ( 1.2 pmol kg(-1) min(-1); IV); ( 2 and 3) s. c. infusion of GLP-1 (2.4 and 9.6 pmol kg(-1) min(-1); LSC, HSC); (4) s. c. infusion of GLP-1 (2.4 pmol kg(-1) min(-1)) in combination with a DPP-4 inhibitor (IB); and ( 5) s. c. infusion of saline (154 mmol NaCl/ l; SAL). Seven patients with type 2 diabetes participated in all protocols. Results: Plasma levels of intact GLP-1 increased from 7 +/- 1 (SAL) to 17 +/- 3 (LSC), 61 +/- 7 ( IB), 62 +/- 5 ( IV) and 94 +/- 10 ( 9.6 s. c.) pmol/ l, p< 0.0001. Plasma concentrations of the metabolite increased from 1 +/- 3 ( SAL) and 2 +/- 6 ( IB) pmol/ l to 42 +/- 4 ( LSC), 64 +/- 8 ( IV) and 327 +/- 16 ( HSC) pmol/ l, p< 0.0001. Mean plasma glucose levels at 6 h decreased from 12.4 +/- 1.1 ( SAL) mmol/l to 10.4 +/- 1.1 ( LSC), 8.6 +/- 0.6 ( IB), 8.8 +/- 0.8 ( IV) and 9.1 +/- 0.9 ( HSC) mmol/ l, p< 0.0001. Conclusions/interpretation: At approximately similar concentrations of intact GLP-1 ( IV, IB, HSC), but with widely ranging metabolite concentrations, the effect on plasma glucose levels was equal, indicating that the presence of the metabolite does not antagonise the glucose-lowering effect of GLP-1.